Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5 years of ACADM sequencing

Emily H. Smith, Cheryl Thomas, David McHugh, Dimitar Gavrilov, Kimiyo Raymond, Piero Rinaldo, Silvia Tortorelli, Dietrich Matern, W Edward Jr. Highsmith, Devin Oglesbee

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.

Original languageEnglish (US)
Pages (from-to)241-250
Number of pages10
JournalMolecular Genetics and Metabolism
Volume100
Issue number3
DOIs
StatePublished - Jul 2010

Fingerprint

Oxidoreductases
Newborn Infant
Genotype
Urine
Screening
Plasmas
Exons
Fatty Acids
Physicians
Genes
DNA
Oxidation
Medium chain acyl CoA dehydrogenase deficiency
Testing
N-caproylglycine
octanoylcarnitine

Keywords

  • Biochemical genetics
  • Fatty acid oxidation
  • Gene sequencing
  • In silico
  • Medium-chain acyl-coA dehydrogenase
  • Newborn screening
  • Variant of unknown significance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Allelic diversity in MCAD deficiency : The biochemical classification of 54 variants identified during 5 years of ACADM sequencing. / Smith, Emily H.; Thomas, Cheryl; McHugh, David; Gavrilov, Dimitar; Raymond, Kimiyo; Rinaldo, Piero; Tortorelli, Silvia; Matern, Dietrich; Highsmith, W Edward Jr.; Oglesbee, Devin.

In: Molecular Genetics and Metabolism, Vol. 100, No. 3, 07.2010, p. 241-250.

Research output: Contribution to journalArticle

Smith, EH, Thomas, C, McHugh, D, Gavrilov, D, Raymond, K, Rinaldo, P, Tortorelli, S, Matern, D, Highsmith, WEJ & Oglesbee, D 2010, 'Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5 years of ACADM sequencing', Molecular Genetics and Metabolism, vol. 100, no. 3, pp. 241-250. https://doi.org/10.1016/j.ymgme.2010.04.001
Smith, Emily H. ; Thomas, Cheryl ; McHugh, David ; Gavrilov, Dimitar ; Raymond, Kimiyo ; Rinaldo, Piero ; Tortorelli, Silvia ; Matern, Dietrich ; Highsmith, W Edward Jr. ; Oglesbee, Devin. / Allelic diversity in MCAD deficiency : The biochemical classification of 54 variants identified during 5 years of ACADM sequencing. In: Molecular Genetics and Metabolism. 2010 ; Vol. 100, No. 3. pp. 241-250.
@article{8431601a993749e1955337b1a09a1abf,
title = "Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5 years of ACADM sequencing",
abstract = "Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or {"}variant of unknown significance (VUS),{"} presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.",
keywords = "Biochemical genetics, Fatty acid oxidation, Gene sequencing, In silico, Medium-chain acyl-coA dehydrogenase, Newborn screening, Variant of unknown significance",
author = "Smith, {Emily H.} and Cheryl Thomas and David McHugh and Dimitar Gavrilov and Kimiyo Raymond and Piero Rinaldo and Silvia Tortorelli and Dietrich Matern and Highsmith, {W Edward Jr.} and Devin Oglesbee",
year = "2010",
month = "7",
doi = "10.1016/j.ymgme.2010.04.001",
language = "English (US)",
volume = "100",
pages = "241--250",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Allelic diversity in MCAD deficiency

T2 - The biochemical classification of 54 variants identified during 5 years of ACADM sequencing

AU - Smith, Emily H.

AU - Thomas, Cheryl

AU - McHugh, David

AU - Gavrilov, Dimitar

AU - Raymond, Kimiyo

AU - Rinaldo, Piero

AU - Tortorelli, Silvia

AU - Matern, Dietrich

AU - Highsmith, W Edward Jr.

AU - Oglesbee, Devin

PY - 2010/7

Y1 - 2010/7

N2 - Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.

AB - Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.

KW - Biochemical genetics

KW - Fatty acid oxidation

KW - Gene sequencing

KW - In silico

KW - Medium-chain acyl-coA dehydrogenase

KW - Newborn screening

KW - Variant of unknown significance

UR - http://www.scopus.com/inward/record.url?scp=77953020257&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953020257&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2010.04.001

DO - 10.1016/j.ymgme.2010.04.001

M3 - Article

C2 - 20434380

AN - SCOPUS:77953020257

VL - 100

SP - 241

EP - 250

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 3

ER -